tbuckley/cabot-search huggingface dataset:
Economic Evaluation of Cost and Time Required for a Platform Trial vs Conventional Trials
Authors: Jay J. H. Park, Behnam Sharif, Ofir Harari, Louis Dron, Anna Heath, Maureen Meade, Ryan Zarychanski, Raymond Lee, Gabriel Tremblay, Edward J. Mills, Yannis Jemiai, Cyrus Mehta, J. Kyle Wathen
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Platform trial design allows the introduction of new interventions after the trial is initiated and offers efficiencies to clinical research. However, limited guidance exists on the economic resources required to establish and maintain platform trials. <h3>Objective</h3> To compare cost (US dollars) and time requirements of conducting a platform trial vs a series of conventional (nonplatform) trials using a real-life example. <h3>Design, Setting, and Participants</h3> For this economic evaluation, an online survey was administered to a group of international experts (146 participants) with publication records of platform trials to elicit their opinions on cost and time to set up and conduct platform, multigroup, and 2-group trials. Using the reported entry dates of 10 interventions into Systemic Therapy in Advancing Metastatic Prostate Cancer: Evaluation of Drug Efficacy, the longest ongoing platform trial, 3 scenarios were designed involving a single platform trial (scenario 1), 1 multigroup followed by 5 2-group trials (scenario 2), and a series of 10 2-group trials (scenario 3). All scenarios started with 5 interventions, then 5 more interventions were either added to the platform or evaluated independently. Simulations with the survey results as inputs were used to compare the platform vs conventional trial designs. Data were analyzed from July to September 2021. <h3>Exposure</h3> Platform trial design. <h3>Main Outcomes and Measures</h3> Total trial setup and conduct cost and cumulative duration. <h3>Results</h3> Although setup time and cost requirements of a single trial were highest for the platform trial, cumulative requirements of setting up a series of multiple trials in scenarios 2 and 3 were larger. Compared with the platform trial, there was a median (IQR) increase of 216.7% (202.2%-242.5%) in cumulative setup costs for scenario 2 and 391.1% (365.3%-437.9%) for scenario 3. In terms of total cost, there was a median (IQR) increase of 17.4% (12.1%-22.5%) for scenario 2 and 57.5% (43.1%-69.9%) for scenario 3. There was a median (IQR) increase in cumulative trial duration of 171.1% (158.3%-184.3%) for scenario 2 and 311.9% (282.0%-349.1%) for scenario 3. Cost and time reductions in the platform trial were observed in both the initial and subsequently evaluated interventions. <h3>Conclusions and Relevance</h3> Although setting up platform trials can take longer and be costly, the findings of this study suggest that having a single infrastructure can improve efficiencies with respect to costs and efforts.
A novel cascaded energy conversion system inducing efficient and precise cancer therapy
Authors: Yong Kang, Na Kong, Meitong Ou, Ying Wang, Qicai Xiao, Lin Mei, Bing Liu, Liqun Chen, Xiaobin Zeng, Xiaoyuan Ji
Journal: Bioactive Materials (2022)

Cancer therapies based on energy conversion, such as photothermal therapy (PTT, light-to-thermal energy conversion) and photodynamic therapy (PDT, light-to-chemical energy conversion) have attracted extensive attention in preclinical research. However, the PTT-related hyperthermia damage to surrounding tissues and shallow penetration of PDT-applied light prevent further advanced clinical practices. Here, we developed a thermoelectric therapy (TET) based on thermoelectric materials constructed p-n heterojunction (SrTiO3/Cu2Se nanoplates) on the principle of light-thermal-electricity-chemical energy conversion. Upon irradiation and natural cooling-induced the temperature gradient (35–45 oC), a self-build-in electric field was constructed and thereby facilitated charges separation in bulk SrTiO3 and Cu2Se. Importantly, the contact between SrTiO3 (n type) and Cu2Se (p type) constructed another interfacial electric field, further guiding the separated charges to re-locate onto the surfaces of SrTiO3 and Cu2Se. The formation of two electric fields minimized probability of charges recombination. Of note, high-performance superoxide radicals and hydroxyl radicals' generation from O2 and H2O under catalyzation by separated electrons and holes, led to intracellular ROS burst and cancer cells apoptosis without apparent damage to surrounding tissues. Construction of bulk and interfacial electric fields in heterojunction for improving charges separation and transfer is also expected to provide a robust strategy for diverse applications.
Evaluation of four chemotherapy regimens for treatment of advanced AIDS-associated Kaposi sarcoma in Kenya: a cost-effectiveness analysis
Authors: Esther E Freeman, Nicole C McCann, Aggrey Semeere, Krishna P Reddy, Miriam Laker-Oketta, Helen Byakwaga, Pamela P Pei, Maya E Hajny Fernandez, Samson Kiprono, Naftali Busakhala, Jeffery N Martin, Toby Maurer, Ingrid V Bassett, Kenneth A Freedberg, Emily P Hyle
Journal: The Lancet Global Health (2022)

The most effective treatment for advanced AIDS-associated Kaposi sarcoma is paclitaxel or pegylated liposomal doxorubicin (PLD); neither is routinely used in sub-Saharan Africa due to limited availability and high cost. We examined the clinical impact, costs, and cost-effectiveness of paclitaxel or PLD in Kenya, compared with etoposide or bleomycin-vincristine.In this study, we use the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-International Model to project clinical outcomes and costs among people living with HIV and advanced Kaposi sarcoma on antiretroviral therapy. We compared four different treatment strategies: etoposide, bleomycin-vincristine, paclitaxel, or PLD. We derived cohort characteristics and costs from the Kenyan Academic Model for Providing Access to Healthcare network, and adverse events, efficacy, and mortality from clinical trials. We projected model outcomes over a lifetime and included life expectancy, per-person lifetime costs, and incremental cost-effectiveness ratios (ICERs). We conducted budget impact analysis for 5-year total costs and did deterministic and probabilistic sensitivity analyses to evaluate the effect of uncertainty in input parameters.We found that paclitaxel would be more effective than bleomycin-vincristine and would increase life expectancy by 4·2 years per person. PLD would further increase life expectancy by 0·6 years per person. Paclitaxel would be the most cost-effective strategy (ICER US$380 per year-of-life-saved compared with bleomycin-vincristine) and would remain cost-effective across a range of scenarios. PLD would be cost-effective compared with paclitaxel if its price were reduced to $100 per cycle (base case $180 per cycle). Implementing paclitaxel instead of bleomycin-vincristine would save approximately 6400 life-years and would increase the overall 5-year Kenyan health-care costs by $3·7 million; increased costs would be primarily related to ongoing HIV care given improved survival.Paclitaxel would substantially increase life expectancy and be cost-effective compared with bleomycin-vincristine for advanced AIDS-associated Kaposi sarcoma in Kenya and should be the standard of care. PLD would further improve survival and be cost-effective with a 44% price reduction.US National Institutes of Health and Massachusetts General Hospital.For the Swahili translation of the abstract see Supplementary Materials section.
Queering global health: a feminist and lesbian, gay, and bisexual perspective – Authors' reply
Authors: Suntosh Rathanam Pillay
Journal: The Lancet Global Health (2022)

We are grateful for the engagement of the Women's Rights Network and LGB Alliance with our Viewpoint, which is, of course, open to scholarly debate and intellectual disagreement. However, we disagree with their criticisms because many of their inferences are an overreach of what our argument is advocating for.
Combating antimicrobial resistance in neonatal infections: a South African perspective
Authors: Dharshni Pillay
Journal: The Lancet Global Health (2022)

The challenge of antimicrobial resistance in neonatal infections in low-income and middle-income countries requires attention. The Article by Rudzani C Mashau and colleagues in The Lancet Global Health provides insights into invasive neonatal infections, including antimicrobial resistance, within the South African public health sector.1 Of note, widespread antimicrobial resistance among neonates, at a population level, has been reconfirmed.
Culture-confirmed neonatal bloodstream infections and meningitis in South Africa, 2014–19: a cross-sectional study
Authors: Rudzani C Mashau, Susan T Meiring, Angela Dramowski, Rindidzani E Magobo, Vanessa C Quan, Olga Perovic, Anne von Gottberg, Cheryl Cohen, Sithembiso Velaphi, Erika van Schalkwyk, Nelesh P Govender
Journal: The Lancet Global Health (2022)

Few population-level estimates of invasive neonatal infections have been reported from sub-Saharan Africa. We estimated the national incidence risk, aetiology, and pathogen antimicrobial susceptibility for culture-confirmed neonatal bloodstream infections and meningitis in South Africa.
Cotrimoxazole guidelines for infants who are HIV-exposed but uninfected: a call for a public health and ethics approach to the evidence
Authors: Brodie Daniels, Louise Kuhn, Elizabeth Spooner, Helen Mulol, Ameena Goga, Ute Feucht, Sabiha Y Essack, Anna Coutsoudis
Journal: The Lancet Global Health (2022)

WHO first recommended cotrimoxazole prophylaxis for all infants who are HIV-exposed but uninfected (HEU) in 2000, given the ability of this treatment to prevent mortality from pneumocystis pneumonia in adults living with HIV. Over the last 21 years, evidence has been generated from the use of cotrimoxazole prophylaxis in infants who are HEU, including two randomised controlled trials, which have shown no clinical benefit and an increase in antibiotic resistance and microbiome dysbiosis. Additionally, improvements in health care over the last two decades in terms of antiretroviral treatment and prophylaxis for mothers and infants, and notably improved vaccination programmes, have substantially reduced the risk of HIV transmission and the overall morbidity and mortality of infants who are HEU from pneumonia and diarrhoeal diseases. Here, we highlight these changes in health care alongside the unchanged cotrimoxazole prophylaxis guidelines and call for a change in these guidelines on the basis of a public health and ethics approach.
Work and health challenges of Indigenous people in Canada
Authors: Quentin Durand-Moreau, Jesse Lafontaine, Jennifer Ward
Journal: The Lancet Global Health (2022)

The Truth and Reconciliation Commission of Canada has published 94 calls to action to redress the legacy of residential schools where thousands of Indigenous children have died. The objective of this narrative review is to address some of these calls by summarising the available evidence on work and health issues encountered by Indigenous workers in Canada. We searched seven databases to retrieve studies on Indigenous people, in Canada, and on occupational health as defined by the International Labour Organization. We included 31 studies, from which we found that Indigenous workers are experiencing intersectionality issues: in addition to having differential health issues related to a below-average socioeconomic status, Indigenous workers face discrimination in workplaces that affects their mental health. Indigenous workers might also cumulate occupational and environmental exposures from industries that have settled close to their dwellings (eg, exposure to polychlorobiphenyls). There is a scarcity of studies on major occupational health topics such as occupational cancers or musculoskeletal disorders in Indigenous people.
PU.1-Dependent Enhancer Inhibition Separates <i>Tet2</i>-Deficient Hematopoiesis from Malignant Transformation
Authors: Maria M. Aivalioti, Boris A. Bartholdy, Kith Pradhan, Tushar D. Bhagat, Aliona Zintiridou, Jong Jin Jeong, Victor J. Thiruthuvanathan, Mario Pujato, Aditi Paranjpe, Chi Zhang, Ross L. Levine, Aaron D. Viny, Amittha Wickrema, Amit Verma, Britta Will
Journal: Blood Cancer Discovery (2022)

Abstract Cytosine hypermethylation in and around DNA-binding sites of master transcription factors, including PU.1, occurs in aging hematopoietic stem cells following acquired loss-of-function mutations of DNA methyl-cytosine dioxygenase ten–eleven translocation-2 (TET2), albeit functional relevance has been unclear. We show that Tet2-deficient mouse hematopoietic stem and progenitor cells undergo malignant transformation upon compromised gene regulation through heterozygous deletion of an upstream regulatory region (UREΔ/WT) of the PU.1 gene. Although compatible with multilineage blood formation at young age, Tet2-deficient PU.1 UREΔ/WT mice develop highly penetrant, transplantable acute myeloid leukemia (AML) during aging. Leukemic stem and progenitor cells show hypermethylation at putative PU.1-binding sites, fail to activate myeloid enhancers, and are hallmarked by a signature of genes with impaired expression shared with human AML. Our study demonstrates that Tet2 and PU.1 jointly suppress leukemogenesis and uncovers a methylation-sensitive PU.1-dependent gene network as a unifying molecular vulnerability associated with AML. Significance: We identify moderately impaired PU.1 mRNA expression as a biological modality predisposing Tet2-deficient hematopoietic stem and progenitor cells to malignant transformation. Our study furthermore uncovers a methylation-sensitive PU.1 gene network as a common feature of myeloid leukemia potentially allowing for the identification of patients at risk for malignant transformation. See related commentary by Schleicher and Pietras, p. 378. This article is highlighted in the In This Issue feature, p. 369
Hypertension in stroke survivors and associations with national premature stroke mortality: data for 2·5 million participants from multinational screening campaigns
Authors: Queran Lin, Tingxi Ye, Pengpeng Ye, Claudio Borghi, Suzie Cro, Albertino Damasceno, Nadia Khan, Peter M Nilsson, Dorairaj Prabhakaran, Agustin Ramirez, Markus P Schlaich, Aletta E Schutte, George Stergiou, Michael A Weber, Thomas Beaney, Neil R Poulter
Journal: The Lancet Global Health (2022)

Blood pressure control has a pivotal role in reducing the incidence and recurrence of stroke. May Measurement Month (MMM), which was initiated in 2017 by the International Society of Hypertension, is the largest global blood pressure screening campaign. We aim to compare MMM participants with and without a previous history of stroke and to investigate associations between national-level estimates of blood pressure management from MMM and premature stroke mortality.In this annual, global, cross-sectional survey, more than 2·5 million volunteers (≥18 years) from 92 countries were screened in May, 2017, and May, 2018. Three seated blood pressure readings and demographic, lifestyle, and cardiovascular disease data were collected. Associations between risk factors and stroke history were analysed with mixed-effects logistic regression, and associations between national-level estimates of blood pressure management and premature stroke mortality based on Global Burden of Disease data were investigated with linear regression.2 222 399 (88·4%) of 2 515 365 participants had recorded data on a history of stroke, of whom 62 639 (2·8%) reported a previous stroke. Participants with a history of stroke had higher rates of hypertension (77·0% vs 32·9%, p<0·0001) and of treated (90·2% vs 57·0%, p<0·0001) and controlled (55·9% vs 32·4%, p<0·0001) hypertension than those without a history of stroke. A third of participants with a history of stroke had either untreated hypertension or treated but uncontrolled hypertension (blood pressure ≥140/90 mm Hg). Strong positive associations were found between national premature stroke mortality and mean systolic blood pressure (84·3 [95% CI 38·8 to 129·9] years of life lost [YLL] per 100 000 people per mm Hg increase) and the percentage of participants with raised blood pressure (49·1 [22·6 to 75·6] YLL per 100 000 people per 1% increase). Strong negative associations were found between national premature stroke mortality and the percentage of participants with hypertension on treatment (-21·0 [-33·0 to -8·9] YLL per 100 000 people per 1% increase) and with controlled blood pressure (-31·6 [-43·8 to -19·4] YLL per 100 000 people per 1% increase).Blood pressure control remains suboptimal worldwide among people with a history of stroke. National estimates of blood pressure management reflect national premature stroke mortality sufficiently to prompt policy makers to promote blood pressure screening and management.International Society of Hypertension and Servier Pharmaceuticals.
Evaluation of Gabapentin and Transforaminal Corticosteroid Injections for Brachioradial Pruritus
Authors: Rodrigo A. Gutierrez, Timothy G. Berger, Vinil Shah, Ritesh Agnihothri, Sibel Demir-Deviren, Marlys S. Fassett
Journal: JAMA Dermatology (2022)

This case series compares the reported outcomes of transforaminal injections and oral medications in patients with a brachioradial pruritus diagnosis.
The efficacy of tucatinib-based therapeutic approaches for HER2-positive breast cancer
Authors: Zaid Sirhan, Anita Thyagarajan, Ravi P. Sahu
Journal: Military Medical Research (2022)

Abstract Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in approximately 15–20% of breast cancer cases. HER2 is a member of the epidermal growth factor receptor (EGFR) family with tyrosinase kinase activity, and its overexpression is linked to poor prognosis and shorter progression-free survival (PFS) and overall survival (OS). Among various treatment options, HER2-targeting monoclonal antibodies and tyrosine kinase inhibitors (TKIs) have mostly been applied in recent decades to treat HER2-positive (HER2+) breast cancer patients. Although positive clinical outcomes were documented in both advanced disease and neoadjuvant settings, the development of resistance mechanisms to such approaches has been one of the major challenges with the continuous usage of these drugs. In addition, patients who experience disease progression after treatment with multiple HER2-targeted therapies often have limited treatment options. The Food and Drug Administration (FDA) has recently approved a new TKI (i.e., tucatinib) for use in combination with immunotherapy and/or chemotherapeutic agents for the treatment of advanced-stage/metastatic HER2+ breast cancer. This review highlights recent updates on the efficacy of tucatinib-based therapeutic approaches in experimental models as well as in the clinical settings of HER2+ breast cancer.
In vivo imaging of calcium dynamics in zebrafish hepatocytes
Authors: Macarena Pozo‐Morales, Inés Garteizgogeascoa, Camille Perazzolo, Juhoon So, Donghun Shin, Sumeet Pal Singh
Journal: Hepatology (2022)

Background and Aims: Hepatocytes were the first cell type for which oscillations of cytoplasmic calcium levels in response to hormones were described. Since then, investigation of calcium dynamics in liver explants and culture has greatly increased our understanding of calcium signaling. A bottleneck, however, exists in observing calcium dynamics in a noninvasive manner because of the optical inaccessibility of the mammalian liver. Here, we aimed to take advantage of the transparency of the zebrafish larvae to image hepatocyte calcium dynamics in vivo at cellular resolution. Approach and Results: We developed a transgenic model expressing a calcium sensor, GCaMP6s, specifically in zebrafish hepatocytes. Using this, we provide a quantitative assessment of intracellular calcium dynamics during multiple contexts, including growth, feeding, ethanol‐induced stress, and cell ablation. Specifically, we show that synchronized calcium oscillations are present in vivo , which are lost upon starvation. Starvation induces lipid accumulation in the liver. Feeding recommences calcium waves in the liver, but in a spatially restricted manner, as well as resolves starvation‐induced hepatic steatosis. By using a genetically encoded scavenger for calcium, we show that dampening of calcium signaling accelerates the accumulation of starvation‐related lipid droplets in the liver. Furthermore, ethanol treatment, as well as cell ablation, induces calcium flux, but with different dynamics. The former causes asynchronous calcium oscillations, whereas the latter leads to a single calcium spike. Conclusions: We demonstrate the presence of oscillations, waves, and spikes in vivo . Calcium waves are present in response to nutrition and negatively regulate starvation‐induced accumulation of lipid droplets.
Why are vaccination rates lower in low and middle income countries, and what can we do about it?
Authors: Hasan Mahmud Reza, Vaishnavi Agarwal, Farhana Sultana, Razmin Bari, Ahmed Mushfiq Mobarak
Journal: BMJ (2022)

Regulation of the neuron–glia cell-fate switch is a critical step in the development of the CNS. Previously, we demonstrated that Lhx2 is a necessary and sufficient regulator of this process in the mouse hippocampal primordium, such that Lhx2 overexpression promotes neurogenesis and suppresses gliogenesis, whereas loss of Lhx2 has the opposite effect. We tested a series of transcription factors for their ability to mimic Lhx2 overexpression and suppress baseline gliogenesis, and also to compensate for loss of Lhx2 and suppress the resulting enhanced level of gliogenesis in the hippocampus. Here, we demonstrate a novel function of Dmrt5/Dmrta2 as a neurogenic factor in the developing hippocampus. We show that Dmrt5, as well as known neurogenic factors Neurog2 and Pax6, can each not only mimic <i>Lhx2</i> overexpression, but also can compensate for loss of Lhx2 to different extents. We further uncover a reciprocal regulatory relationship between Dmrt5 and Lhx2, such that each can compensate for loss of the other. Dmrt5 and Lhx2 also have opposing regulatory control on <i>Pax6</i> and <i>Neurog2</i>, indicating a complex bidirectionally regulated network that controls the neuron–glia cell-fate switch. <b>SIGNIFICANCE STATEMENT</b> We identify Dmrt5 as a novel regulator of the neuron–glia cell-fate switch in the developing hippocampus. We demonstrate Dmrt5 to be neurogenic, and reciprocally regulated by Lhx2: loss of either factor promotes gliogenesis; overexpression of either factor suppresses gliogenesis and promotes neurogenesis; each can substitute for loss of the other. Furthermore, each factor has opposing effects on established neurogenic genes <i>Neurog2</i> and <i>Pax6</i>. Dmrt5 is known to suppress their expression, and we show that Lhx2 is required to maintain it. Our study reveals a complex regulatory network with bidirectional control of a fundamental feature of CNS development, the control of the production of neurons versus astroglia in the developing hippocampus. Finally, we confirm that Lhx2 binds a highly conserved putative enhancer of <i>Dmrt5</i>, suggesting an evolutionarily conserved regulatory relationship between these factors. Our findings uncover a complex network that involves Lhx2, Dmrt5, Neurog2, and Pax6, and that ensures the appropriate amount and timing of neurogenesis and gliogenesis in the developing hippocampus.